Bloom, et al., U.S. Pat. No. 5,061,727, disclose substituted 5-(2-((2-aryl-2-hydroxyethyl)amino)propyl)-1,3-benzodioxoles of general formula (I) ##STR3## wherein R.sub.1 and R.sub.4 may be one or more groups which may be the same or different and are selected from the group consisting of hydrogen, C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, hydroxy, halogen, trifluoromethyl, carboxy, hydroxyalkyl, alkoxycarbonyl, C.sub.1 to C.sub.4 thioalkyl, sulfonyl and sulfinyl; X is a divalent radical consisting of ##STR4## wherein R' is selected from the group consisting of hydrogen, C.sub.1 to C.sub.4 alkyl and C.sub.1 to C.sub.4 acyl and Y is selected from the group consisting of carbonyl and thiocarbonyl; R.sub.2 and R.sub.3 may be the same or different and are selected from the group consisting of hydrogen and C.sub.1 to C.sub.4 alkyl; R.sub.5 and R.sub.6 are selected from the group consisting of hydrogen, carboxy, alkoxycarbonyl, hydroxymethyl, --CH.sub.2 OCH.sub.2 COOR.sub.7 and --CH.sub.2 OCH.sub.2 CH.sub.2 OR.sub.7, where R.sub.7 is hydrogen or C.sub.1 to C.sub.4 alkyl; with the provision that R.sub.5 and R.sub.6 may not both be hydrogen; which have antihyperglycemic and antiobesity activity.
The synthesis, antidiabetic effects, and antiobesity effects of (R,R)-5-2-2-(3-chlorophenyl)-2-hydroxyethyl!amino!propyl!-1,3-benzodiox ole-2,2-dicarboxylate (which is one of the compounds disclosed by Bloom, et al. in U.S. Pat, No. 5,061,727) are detailed in Bloom, et al. J. Med. Chem., 1992, 35, 3081, Largis, et al. Drug Dev. Res., 1994, 32, 69, and Bloom, et al. Drugs of the Future, 1994, 19, 23.
The compounds of the present invention possess greatly increased potency at human .beta..sub.3 receptors in comparison to the compounds in Bloom, et al., U.S. Pat. No. 5,061,727. They retain high selectivity for the P3 receptor and show much higher antiobesity and antihyperglycemic activity in animal models than the compounds of the prior art. The compounds have intrinsic activity at human .beta..sub.3 receptors and can directly bring about antihyperglycemic and antiobesity effects, but may also be hydrolyzed in vivo to deliver a compound of the type disclosed in Bloom, et al., U.S. Pat. No. 5,061,727 where R.sub.5 and R.sub.6 are carboxy. Thus the compounds may act as prodrugs. Therefore, the compounds of this invention are useful in treating diabetes, hyperglycemia, and obesity, exhibiting minimal side effects such as heart rate increase and muscle tremor in humans and animals, when formulated into pharmaceutical compositions.